Genomic diagnosis for children with intellectual disability and/or developmental delay

Kevin M. Bowling, Michelle L. Thompson, Michelle D. Amaral, Candice R. Finnila, Susan M. Hiatt, Krysta L. Engel, J. Nicholas Cochran, Kyle B. Brothers, Kelly M. East, David E. Gray, Whitley V. Kelley, Neil E. Lamb, Edward J. Lose, Carla A. Rich, Shirley Simmons, Jana S. Whittle, Benjamin T. Weaver, Amy S. Nesmith, Richard M. Myers, Gregory S. BarshE. Martina Bebin, Gregory M. Cooper

Research output: Contribution to journalArticlepeer-review

159 Scopus citations


Background: Developmental disabilities have diverse genetic causes that must be identified to facilitate precise diagnoses. We describe genomic data from 371 affected individuals, 309 of which were sequenced as proband-parent trios. Methods: Whole-exome sequences (WES) were generated for 365 individuals (127 affected) and whole-genome sequences (WGS) were generated for 612 individuals (244 affected). Results: Pathogenic or likely pathogenic variants were found in 100 individuals (27%), with variants of uncertain significance in an additional 42 (11.3%). We found that a family history of neurological disease, especially the presence of an affected first-degree relative, reduces the pathogenic/likely pathogenic variant identification rate, reflecting both the disease relevance and ease of interpretation of de novo variants. We also found that improvements to genetic knowledge facilitated interpretation changes in many cases. Through systematic reanalyses, we have thus far reclassified 15 variants, with 11.3% of families who initially were found to harbor a VUS and 4.7% of families with a negative result eventually found to harbor a pathogenic or likely pathogenic variant. To further such progress, the data described here are being shared through ClinVar, GeneMatcher, and dbGaP. Conclusions: Our data strongly support the value of large-scale sequencing, especially WGS within proband-parent trios, as both an effective first-choice diagnostic tool and means to advance clinical and research progress related to pediatric neurological disease.

Original languageEnglish
Article number43
JournalGenome medicine
Issue number1
StatePublished - May 30 2017


  • CSER
  • Clinical sequencing
  • De novo
  • Developmental delay
  • Intellectual disability


Dive into the research topics of 'Genomic diagnosis for children with intellectual disability and/or developmental delay'. Together they form a unique fingerprint.

Cite this